I propose to use molecular modeling techniques to understand the structural and thermodynamic consequences of mutations. The analysis is focused on the GCN4 leucine zipper, a small, very stable peptide that can be used to study the effect of mutations on the structure and stability of protein complexes. I am collaborating with Peter Kim(Whitehead Institute and MIT) and Tom Alber(University of California, Berkeley). Kim's group is providing synthetic GCN4 peptide and thermodynamic stability measurements. Alber's group is providing crystal structures, and I am providing a computational analysis of how the structural modifications result in the observed stability change. This project provides a unique collaboration among three groups, each providing its expertise toward a common goal of understanding protein structure and stability. Based on my analysis, new structures and stabilities will be determined to test the overall theory. This analysis offers prospects for the design of inhibitory peptides or small molecules that would disrupt oncogenic dimer formation.